Considerable effort and resources have been devoted to reducing the burden of cardiovascular disease and mortality rates after acute myocardial infarction have decreased over the past 30 years. However, coronary artery disease remains the leading cause of morbidity and mortality in the developed world. An estimated 79.4 million American adults (1 in 3) have one or more types of cardiovascular disease. Of these, an estimated 1.4 million Americans per year will have a myocardial infarction and another 500,000 present with other forms of acute coronary events that lead to cardiac ischemia. In 2007, an estimated 1.68 million patients were discharged in the US suffering from acute coronary syndrome. In 2004, an estimated 6,363,000 in-patient cardiovascular operations and procedures were performed in the United States. These included an estimated 1,285,000 in-patient angioplasty procedures, 427,000 in-patient bypass procedures and 1,471,000 in-patient diagnostic cardiac catheterizations (see Rosamond et al. (2007) Heart Disease and Stroke Statistics—2007 Update. Circulation. 115:e69-3171).
For patients who suffer from any form of acute coronary syndrome, the heart muscle is deprived of adequate levels of oxygen until appropriate treatment can be initiated. The deprivation can occur for a variable period of time and along a spectrum of severity. In many cases, irreversible damage to the heart can result in infarction, with cell death occurring in one of more areas of the left ventricular or right ventricular myocardium or within the conduction system of the heart. In addition to the effects of this lack of available oxygen on cardiomyocytes and conduction tissue, it has become increasingly recognized that the endothelial cells lining the blood vessels can also be damaged or can become impaired in their ability to function. Furthermore, the recognition of the importance of the endothelial lining of the vasculature has allowed a broader understanding of the resultant microvascular dysfunction that can follow even successful reperfusion of the epicardial or larger arterial or arteriolar supply. This also highlights the need for more appropriate means by which to mitigate post-ischemic patterns of injury.
In human beings with acute coronary insufficiency, ischemia is usually not limited merely to the area supplied by an artery affected by acute occlusion.
Modern treatment of acute myocardial infarction or myocardial ischemia often comprises performing percutaneous intervention on the vessels to facilitate increased blood flow. Coronary interventions typically include procedures that generally require advancing a guiding wire through an artery into a region of obstruction; advancing a catheter including a dilation device such as a balloon over that wire through the offending lesion; and then inflating the device, i.e. the angioplasty balloon, to eliminate the lesion. After deflation, the artery is then open to existing blood flow. Other methods of eliminating lesions include angioplasty with stent deployment, directional atherectomy with or without distal protection, laser therapy, intracoronary declotting and ultrasound devices. Such procedures can all be broadly considered to be part of the clinical arena of percutaneous coronary intervention (PCI).
In the setting of acute coronary events, current ACC/AHA guidelines regarding acute percutaneous coronary interventions exist to determine the timing, among other clinically relevant parameters, of PCI and to steer the operator to (or away from) the heart catheterization lab. These guidelines are based upon the “clinical condition” of the patient and focus largely upon the appearance of an EKG, time from onset of symptoms, the clinical appearance of the patient, including hemodynamic parameters, and, sometimes, other “thrombolysis in myocardial infarction” trial (TIMI) risk factors defined a decade or longer ago. Although guided by well-defined and well-studied clinical indicators, the clinical assessment of a patient with an acute evolving coronary syndrome is known to be imprecise. Often times, a patient may be unclear on when the syndrome began, may have mistaken his or her symptoms for a different condition and may have even attributed them incorrectly to something unrelated to the heart. An assessment of the time from the onset of symptoms and the amount of time that may elapse between the patients' arrival to emergency care and the inflation of an angioplasty balloon can often only be estimated and is highly variable. This lack of precision can predispose to significant, additive cardiac injury that relates to both the inciting syndrome and the approach taken by the clinician. One unintended consequence of the comparatively successful and widespread catheter-based treatment of such acute coronary conditions has been an increase in chronic heart failure related to ischemic cardiac injury. This syndrome is otherwise known as ischemic cardiomyopathy and represents the most common form of congestive heart failure in the U.S. and the developed world in patients with associated left ventricular systolic impairment. Heart failure specialists have, for years; pointed out that in the modern era we have exchanged a reduction in death from acute myocardial infarction for an epidemic of chronic congestive heart failure.
Without modification, the goal of acute PCI therapy during acute coronary events is to reestablish normal blood flow in the narrowed or occluded artery. However, it has become clear that immediate reperfusion with arterial blood in certain circumstances causes extensive, and potentially lethal, reperfusion injury. In fact, because of the realization of the potential for such injury, many patients for whom this invention will benefit would not otherwise be offered immediate reperfusion therapy. Such patients are those in whom the coronary syndrome is known to have been progressing for a considerable period of time. Time to reperfusion, as a result, has become a benchmark standard in the treatment of many such patients. If too much time has elapsed, many patients are treated medically, allowed to “cool-off” and, if they survive, are approached much later after significant damage to the “tissue at risk” has occurred.
Reoxygenation injury can occur after reestablishing blood flow (perfusion) in a previously ischemic tissue. The severity of the ischemic conditions sets the stage for significant oxygen-related and other damage depending upon certain conditions that exist once flow is reestablished or ischemia is eliminated. Even a brief period of abrupt oxygen re-exposure after ischemia can initiate damaging oxidative stress and result in numerous inflammatory responses. Key calcium ion fluctuations triggered by the presence of molecular oxygen that lead to various degrees of contracture can also occur. Countless other molecular mechanisms and pathways, are also involved and may lead to both immediate and delayed cellular injury and swelling within the cytosolic, mitochondrial and sarcoplasmic reticular membranes and can ultimately lead to incremental or catastrophic cellular damage or death. Our understanding in this regard points to thousands of years of evolving mechanisms for tolerating ischemic injury that can be harmful upon exposure to abrupt reperfusion initiating by modern treatment modalities.
Although, several methods have been proposed to combat the effects of this pattern of oxygen and reperfusion-related injury, these have been either misguided or ineffective. For examples, proposed methods includes those aimed at supplying superoxygenated fluids to previously ischemic tissue (see for eg. U.S. Patent Publication No. 2005/0042132) to “force” oxygen into the damaged areas, or methods of reducing the temperature of the reperfusion fluids to reduce metabolic load of the cells. None of these methods has offered a realizable approach to actually preventing or reducing reperfusion-related injury in the population of patients most seriously affected by acute ischemia.
Certain groups have proposed feedback systems to guide reperfusion therapy. For example, U.S. Pat. No. 5,533,957 to Aldea provides a retroperfusion catheter that can be adjusted based on pressure feedback. Similarly, U.S. Pat. No. 6,481,439 to Salient Interventional Systems, Inc. and related cases provide catheters that allow feedback control of a reperfusate based on pressure of the downstream fluids. U.S. Pat. No. 7,218,964 and related cases to Medtronic provide a closed loop system for providing electrical stimulation to the spinal cord to regulate the autonomic nervous system. U.S. Patent Publication No. 2007/0169779 to Freeman provides an apparatus for resuscitating a patient using a ventilator adjustable based on certain tissue parameters. U.S. Patent Publication No. 2006/0142826 to Willard provides a system for targeted delivery of supercooled fluids that can be regulated based on temperature feedback. U.S. Patent Publication No. 2006/0100639 to Levin provides certain methods in which reperfusion therapy is delivered to the patient based on pressure feedback. However, these feedback systems limited to pressure or temperature concerns of the perfusate.
There remains a need for improved methods and apparatus to reduce reperfusion injury. There specifically remains a need for a method and apparatus that provides improved control over tissue conditions that can be linked to catheter-based therapies that do not require surgery or as an adjunct to myocardial protection strategies used during open-heart surgery and acute coronary bypass surgery.
It is therefore an object of the present invention to provide improved methods and apparatuses for controlled reoxygenation of ischemic tissue. It is another object of the invention to reduce reperfusion injury and provide improved patient outcome across a broader spectrum of the population being treated for acute coronary syndrome.